John Jenkins, MD, director of the FDA’s Office of New Drugs, has taken a dim view of the recent––and highly controversial––approval of eteplirsen (Exondys 51, Sarepta Therapeutics) for the treatment of patients with Duchenne muscular dystrophy (DMD), according to a report from FierceBiotech. In a presentation at the National Organization for Rare Disorders (NORD) summit in Arlington, Virginia, Jenkins said that the “path taken by Sarepta is not a good model for other development programs.”
In April, an FDA advisory committee voted 7 to 6 that Sarepta did not provide substantial evidence from “adequate and well-controlled” studies that treatment with eteplirsen could produce dystrophin at a level that was likely to provide a clinical benefit. Much of the data in the company’s new drug application were derived from a small study of 12 children with no placebo control. The study compared the results with eteplirsen against historical data in patients with DMD.
On the question of whether the clinical results of this single study provided “substantial evidence” of eteplirsen’s efficacy, seven panel members voted no; three voted yes; and three abstained.
In September, the FDA granted accelerated approval to eteplirsen for the treatment of patients with DMD. Specifically, the drug was approved for DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects approximately 13% of the DMD population. In its approval statement, however, the FDA noted that a clinical benefit of eteplirsen, including improved motor function, had not been established.
Documents posted by the FDA indicated that Janet Woodcock, MD, director of the agency’s Center for Drug Evaluation and Research (CDER), was the driving force behind eteplirsen’s approval, despite internal protestations from Ellis Unger, MD, a senior official at the agency, among others, to FDA Commissioner Robert Califf, MD. Unger expressed his concerns about the small size of the eteplirsen trial and its lack of clear efficacy, but Woodcock responded that the FDA must be “prepared to be flexible with respect to a devastating illness with no treatment options.” Califf said he would defer to Woodcock in the case and allow the approval.
In his recent presentation, Jenkins made the pointed observation that “flexibility in FDA regulations does not mean marketing approval prior to the demonstration of substantial evidence of effectiveness.”
He added that the FDA’s use of accelerated approvals, such as the one given to eteplirsen, should be prospectively planned, “not as a ‘rescue’ for a failed program.”
In his concluding remarks, Jenkins noted that the FDA’s approval decisions “must be based on data from adequate and well-controlled clinical trials, which may include PROs [patient-reported outcomes] and other patient-derived measures.”